Aminoethylhydrocarbonoxycyclohexenes



Patented Oct. 20, 1953 AMINOETHYLHYDROCARBONOXYCYCLO- HEXENES John A. Hogg, Jerome Korman, William Bradley Reid, Jm, and Alan H. Nathan, Kalamazoo, Mich., assignors to The Upjohn Company, Kalamazoo, Mich., a corporation of Michigan Nonmwing'. ApplicatiomEebruaryZdflQfl Serial! No. 212.5141

Th s: invention re a es. t ,-.-me hi',l =2- Ii-7 subs im ed ami e thy )z hizdreca rb nexr w hexen s: and o a method: for their ro uction. T is! ap li atien s a; ntinuaiionrin-net cineul" emi ra ion: Serial: No, 9.1 511 fi ed catcher 5, 119. s v

The compounds of the present invention have the general structural formula:

g2 cm EEZC/ KGF-H 6L-GBGEFNIR C r H2 wh r in each is a ydrocarbon radical o mining from one to seven carbon atoms, inclusive, such as the methyl, ethyl prop'yl isopropyl, lltyL; sobn y ,,nenty1;. h xy h n l, cr lonronyl, circmhutitll cyclopenty c c QhxyI chemo; and hehzyli radicals. and; the i e. In; the mmu ds Qt this. invent on. the radi als des nat d 3;. air be the. same. or di'fierent hydroc r on adicals- The gr up, RD' is. herein te medie hyd o en,- hanqxy groan, and the Q IQielfI fi em odime t: of Hi m thyl. v The Products of this n nt n. when, t ated with cyanogen bromide, yield quaternary salts w ich, t m, can b deco p se to produce 1- me y1i2'- rom e hw 4 hy roc rbqn xycyclohexenes, as more fully disclosed and claimed in the copending application of John A, Hogg, Serial 212,61'5', filed February 24', I951.

he compoun s of; the pre nt. inven ionv n e. P are sta ing. with a, p a-hydro ar on:

x p qt m oether of hydm uinnni ha n the formula:

wherein R is a: hydrocarbon radical as specified in. the foregoing definition oi" R. Such com.- ponnds readily react with three molecules oi hydrogen in the. presence: of a; nickel czwwlysiivat temperatures between approximately 130 and an proximately 300' degrees centigrade to yield the so u corresponding saturated compound, pgrei-vhgdroca btmoxsgcrelehexenel hating the fo mula;

whichlca ibebxidize eana ie iildm ietbflnq i cxqlohexanone the mimul Row-BE which readi x concerted it m ans of: heatienil Ewe-c d itghss weatherman-threw carbono rcrelch xamne hav g, the mmule I a helc enr uhstir wherein X is a halogen, e. g., chlorine or bromine, and each R is a hydrocarbon radical having the significance hereinbefore assigned. ,e-Diethylaminoethyl chloride is a typical example of such amine. Ordinarily the reaction is conducted in an inert organic solvent, such as benzene, toluene or xylene, at a temperature between approximately 80 and approximately 140 degrees centigrade, and preferably at about the reflux temperature of the solvent employed. The reaction is complete in from 10 to 20 hours, at the end of which time the product, a 2-carbethoxy-2- (B-disubstituted aminoethyl) -4-hydrocarbonoxycyclohexanone having the formula:

c coo-42m H2 wherein the Rs have the significance hGIEiIIbQ-r fore specified, may be isolated in conventional manner, such as by extraction from the organic layer with dilute acid, e. g., hydrochloric or sul-' furic, and subsequent neutralization with alkali, e. g., potassium carbonate or sodium hydroxide. The crude product is then extracted with a solvent such as ether or benzene and isolated by evaporation of the solvent.

The Z-carbethoxy-Z-(s-disubstituted aminoethyl) 4 hydrocarbonoxycyclohexanone thus produced is then decarbalkoxylated, as with hydrochloric or sulfuric acid having a concentration between approximately 10 and approximately 20 percent by weight at a temperature between approximately 80 and approximately 110 degrees centigrade, preferably at about reflux temperature, for a period between approximately 10 and approximately 20 hours, or, alternatively, with barium hydroxide in alcohol, to produce a 2-(18- disubstituted aminoethyl)-4-hydrocarbonoxycyclohexanone having the formula:

mo c=o RO-H H-OH CHz-NR1 wherein the Rs have the hereinbefore assigned significance. After decarbalkoxylation, the

RO-H H-CHzCHz-NR:

wherein the Rs have the hereinbefore assigned significance. The reaction is preferably conducted at the reflux temperature of the solvent employed, and is ordinarily complete in a period of from 2 to 4 hours.

The resulting 1-methy1-2-(fl-disubstituted aminoethyD-4 hydrocarbonoxycyclohexanol is dehydrated by means of a suitable dehydrating agent, such as potassium hydrogen sulfate, thionyl chloride in pyridine, phosphorus tribromide in pyridine, aluminum hydroxide with the cyclohexanol in the vapor phase, and the like, with phosphorus tribromide in pyridine being preferred. Such general procedures are known in the art and are conducted in conventional manner for such dehydrations. The product of the reaction is a 1-methyl-2-(,B-disubstituted aminoethyl) -4-hydrocarbonoxycyclohexene 1 having the formula:

wherein the Rs have the significance hereinbel fore assigned. The reaction product is isolated by conventional procedure, as by dissolving in water, neutralizing with alkali, extracting with ether and subsequently distilling.

The following examples illustrate typical compounds of the present invention and methods by which they may be prepared. It will be understood that changes and modifications may be adopted, as is obvious to those skilled in the art, without departing from the spirit or scope of the invention.

PREPARATION 1.-4:-ME1HOXYCYCLOHEXANOL AND OTHER 4-ALKOXYCYCLOHEXANOLS A solution of 500 grams of a-methoxyphen01 (monomethyl etherof hydroquinone) in 800 milliliters of ethanol was subjected to hydrogen ation in the presence of 165 grams (wet weight) of a Raney nickel catalyst prepared by the method of Adkins and Pavlic [J. Am. Chem. Soc., 68, 147 (1946) l. The initial pressure of the hydrogenation at room temperature was between approximately 1000 and approximately 1800 pounds per square inch and the final temperature was about 140 degrees centigrade. The total time required for the hydrogenation was approximately 2 to 3 hours. After removal of the catalyst and solvent, distillation of the residue gave 445 grams percent) of 4-methoxycyclohexanol as a colorless liquid boiling at 104405 degrees centigrade at a pressure of 13 millimeters of mercury.

In a like manner, 4-ethoxycyclohexanol can be obtained by the hydrogenation of 4-ethoxypheno1 (ethyl ether of hydroquinone); 4-propoxycyclohexanol can be obtained from -propoxyphenol; 4-n-butoxycyclohexanol can be obtained from 4- n-butoxyphenol; and 4-benzyloxycyclohexanol can be obtained from -benzyloxyphenol. These alkoxyphenols (ethers of hydroquinone) can be prepared by the method described by Klarman, Gatyas and Shternov in J. Am. Chem. $00., 54, 298 (1932).

PREPARATION 2.4METHOXYOYCLOHEXANONE AND OTHER 4-ALKOXYGYCLOHEXANONES The oxidation of -methoxycyclohexanol (Preparation 1) was carried out according to the procedure of Helfer [Helv. Chim. Acta, 7, 953 (1924) 3. To a solution of grams of potassium dichromate in grams of sulfuric acid and 400 milliliters of water cooled in an ice-bathwa's.

added with vigorous stirring 58.5 grams of 4- easaaae PREPARATION 3.--2-CABBETHOXY. 4. METHOXYCYCLO- HEXANONE AND OTHERHZ-OQRBALKOXYA-METHYD GYCLOHEXANONES The preparation"orthiscompound' was carried out by the method heretofore described for the preparation of 2-carbethoxycyclohexanone (SnydenrBiookssanddshapirop Org; Syntheses;::;.Coll.-: vol:iIlKUdhmzWileyraandrSbnss NiewsYorkz:.1943.;ipz

531i;:cfsiCoob-andLaurencewJ; Clieme Soc.,.,1938, 58). To a. SOIUfiEOII'Df AQigl ZJmSlZ.1110185) sof:s'odi.-:-, umuinasfilljoimilliliters .of -absolutetaethanol .insan ice-salt bath was addedaatclOrdegreesscentigrade withii vig'orousssstirrings as cold visolution f. 256 grams (2 moles) of 4- .methoxyoyelohexanone. (Preparatioirs2 3;: imi292-z-"grams (2 moles} -o1ethyl oxalate during a period ofi:rrto.20@minutesr The mixture ewaszstirredzat ice bathrtemperature for 1 hour and at room temperaturasfor-z-about:16'

hours; aeidiiiedewitlnziceacoldisulfuriclsaoidgi and extracted with benzene. Afterrremo ialsof;:the benzene-aoriasteaurebath about tg1zamsrzofipowdered soft glass was addedszctonthesresidualzc2: ethoxazlyla iemethoxycyclohexanone .andihe anixwas heated to 150 degrees centigradeawith.stir,- ring at a subatmosphericz pressure. of approximately millimeters iofmercury-luntil the evolutionziofiicarbomzmonoxide .had.;'ce ased. Distillation of the residue-igaye.132Aagrams, (33 percent) of 2-carbethoxy-4-methoxycyclohexanone as a heavy yellow oiltwhiomzboiledeatzlOO-lOE degrees centigrade at a pressure of 1.2 millimeters of mercury.

.In a like manner, 2-carbethoxy-4-ethoxycyclohexanone can be obtained by the ethoxalylation of 4-ethoxycyclohexanone followed by decarbonylation of the 2-ethoxalyl-4-ethoxycyclohexanone; Z-carbethoxy 4 propoxycyclohexanone can be obtained from 4-propoxycyclohexanone; 2 carbethoxy-4-n-butoxycyclohexanone can be obtained from 4-n-butoxycyclohexanone; and 2-carbethoxy-4-benzyloxycyclohexanone can be obtained from 4-benzyloxycyclohexanone.

PREPARATION 4.2-cARBErHoxY-2-(fl-DIETHYLAMINO- ETHYL)1METHOXYOYCLOHEXANONE AND OTHER 2- CABBALKOXY-2- (B-DIETHYLAMINOETHYL) 4-ALK0XY- cYcLoHExANoNEs To a suspension of 2.3 grams (0.1 mole) of sodium sand in 200 milliliters of anhydrous toluene was added dropwise with stirring a solution of 20.0 grams (0.1 mole) of 2-carbethoxy-4-methoxycyclohexanone (Preparation 3) in 25 milliliters of anhydrous toluene. After the addition, the mixture was heated under reflux with stirring for 3 hours, and then stirred overnight at room temperature. The suspension of the sodio derivative was again heated to boiling and to it was add'eiiiflropwis'e, withzsti-rringlsdurin'g-b houses a= sol-utidn of 13:6 .igramsi-l 0.1 mole); of'ifi-diemliii aminoethylmchloride 253. rrr'illiliters .zoffianhwe drbus; toluene. r Afteneheatingeiunden': I'flfiXiifOr-t an additional-1'7 "fhours; Lthe -mixtureewas: cooled and 1 extracteds' withl diiute hydrochloride acids The acid extractwasneutralizediwithisodiumahyi drox-ide soluti'ong saturatedifwithisolid potassium carbonate: and extracted iwitheether; The.-.:ethers. extraetsw-were#washdtvithl aterzz andsdriedglandu' theether 1 waswevaporatedm Distillatiorwoffithes residue gave aafir' percent yieldfl'of flf-icarbethoxyrs 2 ([3 diethylaminoethyl) -4-methoxyeycldhexasr none as amearlycolorless liquidwhichaboiledfiat 132 135- deg-reeswentigrade atria-pressure 0f.-015g millilneter ofmercury; n o=li4ll5ia In a lik-mannerp 2icarbethoxyw (fl-idi nebue. tylaminoeth yld 4 ber-izyloxycyclohexanoneacmr be obtained by the alk-ylatiomofz earbethoxy i benzyloxycyelohexanone: with di.-n=butylamino-': ethyl-chloride;xwhioh can be preparedfiaecordiiig t0 the procedures of Barnett etal.= *[JaAiheOliemr s c.,., 59,. 22485419351] -.and-..B1ic.ke and Maxwe i [ibid., 64, 428,;(194211;,ands2scarbethoxy-2-(p 1 dibenzylaminoethyl) 4 n-butoxycyclohexanone can-be --obtained-by"the :alkylation of '2 -carb'ethox-y s 4=-- n--but0xycyclohexanone'-'with dibenzyl;-"- aminoethyl chlor-ida which can be preparedaccording to the prooedure of Dupreet al.*(JS Chenr A 'solution of 117.0 grams;:(005 mole)- of 2=car#- bethoxyis 2 $-4 9sdiethylaminoethyll- 4 methoxycyclohexanone (Preparation :4)' in =250 millilitera of 20 percen-t sulfuric' acid was-heated underre flux for: 18 hours. Afterowling; the solution was neutralized with sodiiimv hydroxide;-- saturated w-itli'w soli'd: potassium carbonate andextracted Witlrreth'er; The etherextractswerewashed witli water-iand dried;- and iihe ether was =evaporated5 Distillation of .the residue gave *a- 76 peroent yield ofe 24 (B-diethylaminoethyl)fiwi methbxyeyelohex anoneeasea scolorlessaoil whichl boiled at 112 1l4- degreesicentigrad-iatiapressureof 0:8 millimeten of mercury; n =1.4680. The product formed a crystal-Iine..salt with: :oxa-l-ic acid which -melteel' at 1ll+llzidegreescentigrades Analysis (Oxalate). Calculated forO-i'aHttGliN? C, 56.76; H, 8.58; N, 4.41. Found: C, 56.89; H, 8.58; N, 4.36.

In a like manner, 2-(,s-di-n-butylaminoethyl)- 4-benzyloxycyclohexanone can be obtained from 2 carbethoxy 2 (,B-di-n-butylaminoethyl)-4- benzyloxycyclohexanone; and 2-(fi-dibenzylaminoethyl-4-n-butoxycyclohexanone can be obtained from 2 carbethoxy-2-(fi-dibenzylaminoethyl) -4-n-butoxycyclohexanone.

PREPARATION 6.1-METHYL 2 (p-DIETHYLAMINO- ETEYL)-4-METHoxYcYeLoHExANoL-1 AND OTHER 1- METHYL 2 (fl-DIALKYLAMmoETHYL)-4-ALKoxY- oYoLoHExANoLs A solution of methyl lithium in milliliters of anhydrous ether was prepared from 1.1 grams (0.16 mole) of lithium and 9.9 grams (0.07 mole) of methyl iodide. Excess lithium was removed by filtration under a nitrogen atmosphere. To the solution of methyl lithium, under a nitrogen atmosphere, was added dropwise with stirring a solution of 7.0 grams (0.034 mole) of 2-(p-diethylaminoethyl) 4 methoxycyclohexanone (Preparation 5) in 25 milliliters of anhydrous ether. When the addition was complete, the mixture was heated under reflux for 2 hours, cooled and poured onto ice. The ether layer was separated, and the aqueous layer, after saturation with solid potassium carbonate, was ex tracted with ether. The combined ether fractions were washed with water and dried, and the ether was evaporated. Distillation of the residue gave an 87 percent yield of l-methyl-z-(odiethylaminoethyl)-4-methoxycyclohexanol-l as a colorless oil which boiled at 90-92 degrees centigrade at a pressure of 0.03 millimeter of mercury; n =1.4750.

Analysis Calculated for C14H29O2N: C, 69.09; H, 12.01; N, 5.76. Found: C, 68.97; H. 12.48; N, 5.77.

In a like manner, 1-methyl-2-(fl-di-n-butylaminoethyl)-4-benzyloxycyclohexanol-l can be obtained from 2-(5 di n butylaminoethyl) -4- benzyloxycyclohexanone; and l-methyl-2-(fl-dibenzylaminoethyl) 4 n-butoxycyclohexanoll can be obtained from 2-(fi-dibenzylaminoethyl) 4-n-butoxycyclohexanone.

Example 1.1-methyZ-2-(o-diethylaminoethyl) 4-methOxycyclohexene-1 To a solution of 12.1 grams (0.05 mole) of lmethyl-Z-(fi diethylarninoethyl) -4-methoxycyclohexanol-l (Preparation 6) in 20 milliliters of anhydrous pyridine and 40 milliliters of anhydrous benzene maintained in an ice-bath, was added dropwise with stirring a solution of 8.0 grams of phosphorus tribromide in 20 milliliters of anhydrous benzene. When the addition was complete, the orange mixture was stirred overnight at room temperature. It was poured into water, stirred until solid material had dissolved, saturated with solid potassium carbonate, and extracted with ether. Removal of the solvents by distillation and distillation of the residue gave an 80 percent yield of l-methyl-Z-(fl-diethylaminoethyl) -4-methoXycyclohexene-1 as a colorless oil which boiled at 85-87 degrees centigrade at a pressure of 0.12 millimeter of mercury; n =1.4730. The product formed a crystalline salt with oxalic acid which melted at 111-112 degrees centigrade and a crystalline salt with methyl iodide which melted at 130-132 degrees centigrade.

Analysis (Oxalate). Calculated for CmI-IzQOsN: C, 60.93; H, 9.27; N, 4.44. Found: C, 60.83; H. 9.38; N, 4.70.

Analysis (Methiodide). Calculated m1- 1 ClSHBOONIZ C, 49.04; H, 8.23. Found: C, 49.07; H, 8.03.

Other examples 1. A l-methyl-2-(fi aminoethyl) -4-hydrocar-v bonoxycyclohexene having the formula:

H: /O\CHa Etc 5 wherein each R is a hydrocarbon radical containing from one to seven carbon atoms. inclusive.

2. A l-methyl 2 -(,8 di lower alkylaminoethyl) -4=-lower-alkoxycyclohexene.

3. A l-methyl 2 -03 di lower alkylaminoethyl) 4-methoxycyclohexene.

4. A 1 methyl Z-(B-dibenZyIaminOethyD- ilower-alkoxycyclohexene.

5. A l-methyl-Z -(fi-di-n-butylamlnoethyl)- 4- lower-alkoxycyclohexene.

6. A 1 methyl 2-(5 diethy1aminoethyD-4- lower-alkoxycyclohexene.

'7. 1-methyl-2- (B-diethylaminoethyl) 4-methoxycyclohexene-l.

8. 1-methyl-2-(fi di n-butylaminoethyD-4- benzyloxycyclohexene-l.

9. l-methyl 2-(5 dibenzylaminoethyl) -4-nbutoxyoyclohexene-l.

JOHN A. HOGG. JEROME KORMAN. WILLIAM BRADLEY REID, JR. ALAN H. NATHAN.

No references cited. 

1. A 1-METHYL-2-(B-AMINOETHYL)-4-HYDROCARBONOXYCYCLOHEXENE HAVING THE FORMULA 